Fusobacterium bacteremia presenting with inferior mesenteric vein thrombosis

Key Clinical Message Isolated mesenteric vein thrombosis associated with Fusobacterium is rare. Physicians should be aware regarding the association of Fusobacterium with thrombosis at various sites.


| INTRODUCTION
Fusobacterium species are fastidious gram-negative anaerobes generally found as commensal flora in the human oropharyngeal microbiome. 1 The most common species isolated within this genus are F. necrophorum and F. nucleatum, the former is more commonly known to cause Lemierre's syndrome. 2 Variants of Lemierre's syndrome caused by Fusobacterium species have also been described in multiple anatomic locations such as hepatic veins, ovarian veins, suprahepatic veins, and mesenteric veins. [3][4][5][6] Mesenteric vein thrombosis (MVT) is a rare condition that accounts for one in 5000 to 15,000 hospital admissions and one in 1000 admissions to the emergency department, with high mortality (19%-23%). 7 Primary or idiopathic MVT accounts for 21%-49% of the cases and the proportion of patients with idiopathic cases decreases with more extensive evaluation. 8 MVT can occur as a complication of appendicitis, cholecystitis, pancreatitis, diverticulitis, and other intra-abdominal infections. 9 Prothrombotic states or thrombophilia and local intra-abdominal infections are the main causes of MVT. 10 In a study on 22 cases of Fusobacterium-related pylephlebitis, 41% involved only the portal vein, 32% involved some combination of the portal vein, superior mesenteric vein (SMV), inferior mesenteric vein (IMV), or splenic vein, and 14% involved SMV alone. There was isolated involvement of the right hepatic vein in two cases and only in one case was the IMV affected. 9 Hereby, we report a case of a 59-year-old male who presented with a week of back pain and malaise, found to have an acute inferior mesenteric vein thrombosis and blood culture ultimately growing Fusobacterium species who responded well to medical therapy.

| CASE REPORT
A 59-year-old Caucasian male with a 10-year medical history of hypertension and obesity presented to the emergency department complaining of bilateral lower back pain and malaise for 1 week followed by shortness of breath of 1 day duration. The patient denied nausea, vomiting, abdominal pain, fever, flank pain, and urinary symptoms. He described back pain as moderate in intensity and achy in nature, with no alleviating or aggravating factors. He reported no surgical history nor any known history of malignancy or thrombotic disorders in the family. He denied using tobacco and illicit drugs and reported occasional alcohol consumption (approximately 6-8 units per week).
In the emergency department, the patient was afebrile, tachycardic at 121/min, blood pressure 132/82 mm Hg, and oxygen saturation was 96% in room air. Laboratories demonstrated leukocytosis, hyperbilirubinemia, and transaminasemia. Blood cultures were sent. An abdominal ultrasound showed no ductal dilation of the gallbladder; however, the gallbladder was poorly seen. A contrast-enhanced computerized tomography (CT) of the abdomen and pelvis demonstrated an acute/early subacute partially occlusive thrombosis of the IMV with mild adjacent stranding. (Figure 1) There was no evidence of liver abscess, diverticulitis, or colitis. Vascular surgeons were consulted, and the patient was started on apixaban 10 mg twice daily and was discharged on the same dose with a plan to transition to 5 mg twice daily after a week. The anaerobic bottle showed Fusobacterium and the aerobic bottle showed no growth. Emergency department providers made multiple attempts to contact the patient but were unsuccessful.
Only 2 weeks later, the patient returned to the ED with similar symptoms. The patient did not receive any antibiotics between the previous visit and second visit as the providers were unable to reach the patient via phone. In the emergency department, the patient was afebrile, tachycardic at 130/min, blood pressure of 120/84 mm Hg, and oxygen saturation was 96% in the room air. Laboratories were significant for leukocytosis and thrombocytosis. There was no evidence of urinary tract infection on urinalysis. He tested negative for the influenza virus and COVID-19 virus. The urine drug test was negative. The chest CT showed no evidence of pulmonary emboli or acute pulmonary process. Laboratory and imaging workup on admission has been summarized in Table 1. Given the recent mesenteric thrombus, the patient was continued with apixaban 5 mg twice daily. The patient was started on intravenous piperacillin-tazobactam per infectious disease physicians' recommendations. As the evaluation of an underlying hypercoagulable state would not alter the course of immediate treatment of the thrombus and could ultimately be affected by Fusobacterium bacteremia, the hematologist recommended that the workup be performed outpatiently. The medical team also felt that the thrombocytosis was likely reactive in nature, as the patient's platelet count was within normal limits at his previous visit. His clinical course improved and repeated blood cultures were negative twice. After a five-day hospital stay, the patient was discharged with amoxicillin-clavulanic acid (875/125 mg) twice daily for a total duration of 4 weeks and apixaban 5 mg twice daily (HASBLED score-2), with duration to be determined by the hematologist at the outpatient follow-up.
At the follow-up appointments, he was doing well on antibiotics and anticoagulation. Laboratories were significant for the resolution of leukocytosis, thrombocytosis, and transaminitis. (Table 1 for laboratory work on admission and follow-up visit) A repeat CT abdomen/ pelvis 2 months after discharge revealed a diffusely atretic F I G U R E 1 CT abdomen/pelvis 3D coronal view demonstrating acute/early subacute partially occlusive thrombosis of the inferior mesenteric vein with mild adjacent perivascular stranding.
inferior mesenteric vein but no obvious thrombus compared to the previous scan. (Figure 2) The BCR-ABL and JAK2 panel mutations (JAK2 V617F, JAK2 EXON 12-13, Calreticulin, MPL) were negative. A referral was provided to the gastroenterologist for a colonoscopy. The patient was explained that IMV thrombosis was likely due to the underlying Fusobacterium infection, making the thromboembolism a provoked one, and that he would only need 3 months of anticoagulation, which he had completed at the time of his second appointment with the hematologist. No further workup or follow-ups for hematology were recommended.

| DISCUSSION
Fusobacterium necrophorum is a nonspore-forming, obligate anaerobic, gram-negative bacillus and is unique for its ability to cause severe infection. Pylephlebitis, or suppurative thrombophlebitis of the portomesenteric venous system, is a rare complication of intraabdominal infections and is an exceedingly rare sequela of Fusobacterium spp. septicemia. 11 The association between F. nucleatum and thrombosis, although less established, has been reported in several cases, including those of the iliac, portal, and mesenteric veins. [12][13][14][15] The T A B L E 1 Laboratory parameters with reference range.

Laboratories
First emergency visit spread of Fusobacterium to the large intestine and associated vasculature has been proposed to occur via a hematogenous route and translocation from the oral cavity to the intestine. 1 At the molecular level, Fusobacterium species bind and invade various cell types and stimulate inflammatory responses. 16 The adhesin protein, Fusobacterium adhesin A (FadA), binds the cadherins of colonic epithelial cells and vascular endothelial cells, facilitating adherence and invasion of these species. 17,18 F. nucleatum has also been demonstrated to induce inflammatory host cytokines, including IL-6, IL-8, and TNFα. 18 These combined effects create a platform for endothelial cell dysfunction and inflammation, thus promoting thrombus formation. F. nucleatum has been shown to promote colorectal carcinogenesis through direct effects on the expression of oncogenic and inflammatory genes, as well as through suppression of host immunity. 1 Thrombosis in atypical locations warrants consideration of a hypercoagulable state (e.g., malignancy and rheumatological conditions) and colonoscopy for colon cancer and inflammatory bowel disease. 1,19 Diagnosis of mesenteric vein thrombosis is based on confirmatory imaging findings of the portal vein or mesenteric vein thrombosis in the setting of systemic infection. Intravenous contrast-enhanced computerized tomography (CT), ultrasonography, or magnetic resonance imaging (MRI) can all be used to establish the diagnosis, with the former reported as the modality of choice given its availability and high sensitivity. 20 However, despite increasing evidence of the association of Fusobacterium with thrombosis, blood cultures are not consistently included as part of the standard evaluation. 1 Initial evaluations including urinalysis, CT chest/abdomen/pelvis, abdominal ultrasound, and echocardiogram were unremarkable revealing no source of infection. Neck CT was considered, but was ultimately canceled because infectious disease consultants felt that the patient did not reveal signs or symptoms of oral infection with respect to Lemierre's syndrome.
The management of this entity is the timely initiation of antibiotics and anticoagulation. Antibiotic therapy with anaerobic coverage must be rapidly introduced. Mortality is difficult to estimate but can be high, up to 25%, and depends on the timing of antibiotic initiation. 21 As penicillinresistant strains have been reported, empiric therapy should consist of clindamycin or metronidazole or the use of a combination of beta-lactams with beta-lactamase inhibitors. 22 Unlike Lemierre's syndrome, anticoagulation is recommended for all cases of acute or subacute mesenteric vein thrombosis and remains the cornerstone of treatment. 23 A retrospective study of 120 patients with MVT diagnosed between 2000 and 2015 by Salim et. al in 2018 concluded that immediate anticoagulation is an effective first-line therapy in patients with MVT. 23 Anticoagulation should be initiated as soon as the diagnosis of IMV is made, even intraoperatively or in the presence of bleeding as it has been shown to significantly improve survival. 8 Recurrence most commonly occurs in the first 30 days after presentation. The reported rates of 0%-25% can be decreased to 0%-3% in patients who continue on anticoagulation. 24,25 Overall, there is a trend to benefit from early anticoagulation due to the risk of bowel ischemia and infarction, especially when a mesenteric branch is involved. 11 Thrombus formation and rapid bacterial growth can cause septic embolization at distant sites, including the lungs, joints, bones, skin, and soft tissues, muscles, liver, spleen, kidneys, heart, and brain. 3 The timely initiation of anticoagulation may reduce septic embolization of the liver from infected portal thrombi and prevent liver abscesses. 3 In a retrospective study of MVT patients, 13 patients seen before 1995 who did not receive anticoagulants were compared with 28 patients seen after 1995 who received anticoagulants. The patients in the latter group had a shorter mean hospital stay duration (13 vs. 26 days), reduced hospital mortality (11% vs. 39%), and less need for surgery (33% vs. 85%). 26 Choices F I G U R E 2 CT abdomen/pelvis 3D coronal view showing atretic appearance of the inferior mesenteric vein compared to the prior study along with resolution of previous perivascular stranding.
of anticoagulation include unfractionated heparin in the acute setting, which later transitioned to low molecular weight heparin, warfarin, or direct oral anticoagulants (DOAC). 27 Lifelong anticoagulation should be considered in IMV thrombosis cases with persistent hypercoagulable state, irreversible systemic condition, or idiopathic cases. 8 In a case of portal vein thrombosis with underlying Fusobacterium pylephlebitis, warfarin anticoagulation was performed for 6 months with improved clinical outcome. 14 Several clinicians have felt comfortable using DOAC for mesenteric vein thrombosis. Cheng et al. have reported the use of rivaroxaban for 3 months in their case of mesenteric and portal vein thrombosis with Fusobacterium nucleatum bacteremia. 1 Lazar et al. have treated a case of portomesenteric thrombosis secondary to Fusobacterium with apixaban 5 mg twice daily for 3 months with an uneventful course and no bleeding events. 9 Thus, in the absence of any contraindications or presumed risk, anticoagulation therapy should be considered. A duration of 3-6 months of anticoagulation is recommended for patients with reversible causes like the patient described above with an evaluation of risks and benefits. Surgical intervention is reserved for cases with persistent septic emboli, showering, or continued propagation of thrombosis. 28

| CONCLUSION
Fusobacterium is a clinically important yet underrecognized contributor to venous thrombosis at many anatomic sites. Prompt antibiotic therapy, supportive care, and anticoagulation therapy with DOAC for 3 months resulted in a favorable outcome in our case. In patients with portomesenteric thrombosis, blood cultures should be consistently included as part of the standard evaluation, especially when there are vague systemic complaints such as malaise, fatigue, etc. and suspicion of underlying infection. The consequences of untreated MVT can be debilitating, including sepsis and death; therefore, our aim is to increase the awareness of physicians of Fusobacteriumassociated mesenteric vein thrombosis that requires immediate antibiotics and anticoagulation.

ACKNOWLEDGMENTS
This manuscript had been made available as the preprint previously.

FUNDING INFORMATION
No funding was received for this study.

CONFLICT OF INTEREST STATEMENT
None to declare.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
Ethical approval is not required for this study in accordance with local or national guidelines.

CONSENT
Written informed consent was obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editor in chief of this journal on request.